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HHMI: WHAT ARE SOME RECENT ADVANCES?
KH: The ADA-SCID work of Milanese scientists was an important success. These researchers, in clinical trials that began 5 years ago, used a retrovirus to deliver the gene encoding adenosine deaminase (ADA) to six children. Today, all six kids are able to lead normal healthy lives, with no need for treatment and no overt symptoms. This result has been largely ignored in "bad news" stories of gene therapy.
More recently, other researchers have used zinc-finger DNA-binding and -cleaving proteins ["zinc finger" refers to the proteins' shape and composition] to correct errors in a gene that lead to another form of severe combined immune deficiency known as X-linked SCID. That technology for gene correction is promising because it could be adapted into different strategies for fighting many immunodeficiency conditions, including HIV.
And last year scientists published research using a viral vector to loop out the mutant part of the dystrophin protein that's implicated in some forms of muscular dystrophy. Together, these results show that the field is moving forward.
HHMI: WHAT IS THE STATUS OF YOUR OWN RESEARCH?
KH: We have cured hemophilia in lab mice and dogs by injecting them with the gene for Factor IX wrapped in a vector called adeno-associated virus (AAV). Over the past few years, however, humans in clinical trials have expressed therapeutic levels of Factor IX for only a few weeks following vector infusion. That's probably because the patients' immune systems killed the cells hosting the inserted gene. To overcome this problem, we've been working on transiently suppressing the immune response to the viral vector AAV.
HHMI: EXPENSIVE GENE-THERAPY RESEARCH NEEDS INDUSTRIAL SUPPORT, BUT DOESN'T INDUSTRY'S IMPATIENCE ADVERSELY AFFECT THE FIELD'S PROGRESS?
KH: Early safety studies have been slow and time-consuming, and that pace indeed tests the patience of some companies, which exist, after all, to make money for shareholders. But as safety issues are resolved, testing proceeds more quickly—and we are now entering that era.
Meanwhile, we're witnessing the dropout of small biotech companies in gene therapy—and the entry of willing replacements. This shortfall in resources must be addressed by the disease foundations and by federal support for early development of novel therapies.
HHMI: WHAT IS MOST CHALLENGING ABOUT BEING A LEADER IN GENE THERAPY?
KH: It's in imparting a sense of the field's momentum to outside people such as foundation officers and NIH institute directors, who often remain unaware of our progress after having been saturated with negative media coverage of gene therapy. Poor public perception works against us, translating into reluctant funding agencies and clinical trial participants.
During the year I served as president of the American Society of Gene Therapy, the best thing I did was to lead a stakeholders' conference aimed at answering the question: What's slowing down gene-therapy research? We asked scientists to share 15-minute stories of their recent research, sketching what worked and what didn't. From that, we identified several of the field's key hurdles. One of them is the financing of clinical trials, a lost middle ground when pharmaceutical companies want to pick up phase III projects and NIH wants to fund early-stage, or phase I, research. Another challenge is the complex regulatory process governing gene-therapy protocols.
Despite these hurdles, though, there is no question that gene therapy ultimately will succeed. We have to walk before we can run. But we're going to get there.